The challenge of ultra-rarity: Dual diagnosis of Lafora disease and developmental encephalopathies linked to TRIO and SHANK3 pathogenic variants

Abstract

We report two cases of dual genetic diagnoses involving Lafora disease (LD) and co-occurring neurodevelopmental disorders caused by pathogenic variants in TRIO and SHANK3, respectively. LD is an ultra-rare, autosomal recessive, severe form of progressive myoclonus epilepsy affecting previously healthy children or adolescents. In both patients, the presence of developmental delay, intellectual disability, and behavioral abnormalities was consistent with a primary genetic disorder-TRIO-related neurodevelopmental disorder in one, and Phelan-McDermid syndrome in the other. However, the onset of epilepsy with atypical features, coupled with progressive neurological decline in one patient and a positive family history of LD in the other, prompted the additional diagnosis of LD. These cases illustrate how overlapping clinical presentations can obscure the presence of concomitant genetic conditions, potentially delaying diagnosis and appropriate management. Our findings underscore the importance of considering dual diagnoses and show that phenotypical variability in ultra-rare disorders such as LD may be influenced by concurrent genetic conditions. PLAIN LANGUAGE SUMMARY: This report describes two patients who have both Lafora disease, an ultra-rare, progressive type of epilepsy, and other rare genetic disorders that affect development and behavior. In one case, the patient showed a progressive and unusual neurological deterioration, while the other had atypical epileptic seizures and a family history of Lafora disease. These cases highlight how different genetic conditions can share similar symptoms, making it difficult to identify all the issues a patient may have. Understanding these overlaps is important for proper diagnosis and treatment.

Keywords: Phelan‐McDermid syndrome; double trouble; next‐generation sequencing (NGS); progressive myoclonus epilepsy; whole‐exome sequencing (WES); whole‐genome sequencing (WGS).

FIGURE 1

Polygraphy (Case#1). The EEG shows diffuse background slowing and frequent interictal generalized epileptiform discharges. A prolonged, high‐amplitude generalized polyspike‐and‐wave discharge is observed, accompanied by diffuse phasic activity on surface EMG with agonist–antagonist co‐contraction, corresponding to a generalized myoclonic seizure. Delt, deltoid; Flex, forearm flexors; Ext, forearm extensors; L, left; R, right.

FIGURE 2

Muscle Biopsy (Case#1). (A) Hematoxylin and eosin staining showed multiple fibers characterized by subsarcolemmal accumulation of basophilic material (black arrow), also present like multiple dots in the cytoplasm (white arrows). (B) Periodic acid Schiff (PAS) staining showed that the aggregates of basophilic material contained in the fibers were strongly reactive with PAS (black arrows), thus indicating their nature of polyglucosan aggregates consistent with Lafora bodies.

FIGURE 3

EEG (Case#2). Video‐EEG recording started during a prolonged seizure (15 min after clinical onset with generalized hypotonia and loss of consciousness), showing (A) posterior rhythmic delta activity with superimposed fast discharge, prevailing on the right occipital channels. The ictal discharge attenuates two minutes following rectal diazepam administration (B), and is interrupted after 6 min (C). On the MKR channel the period of the square‐wave corresponds to 1 s and its amplitude corresponds to 100 μV. Only a reduced number of electrodes are available; the montage is composed by eight referential channels (average reference) followed by eight longitudinal bipolar channels then three transverse bipolar channels; please note that due to technical issues electrode T3 is malfunctioning, so all related channels (asterisk) are flattened.